Substituted cycloalkyl-4-Oxonicotinic carboxamides; gaba brain receptor ligands

ABSTRACT

Disclosed are compounds of the Formula:                    
     or the pharmaceutically acceptable non-toxic salts thereof wherein: 
     the C ring is a(n) (un)substituted carbocycle; 
     X is hydrogen, hydroxyl or lower alkyl; and 
     W is (un)substituted alkyl, aryl, arylalkyl, or heteroaryl, 
     which compounds are highly selective agonists, antagonists or inverse agonists for GABAa brain receptors or prodrugs of agonists, antagonists or inverse agonists for GABAa brain receptors. These compounds are useful in the diagnosis and treatment of anxiety, sleep and seizure disorders, overdose with benzodiazepine drugs and for enhancement of memory.

This application claims the benefit of provisional application60/076,022, filed Feb. 26, 1998.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to certain substituted cycloalkyl-4-oxonicotiniccarboxamides. In particular it relates to such compounds thatselectively bind to GABAa receptors. This invention also relates topharmaceutical compositions comprising such compounds. It furtherrelates to the use of such compounds in treating anxiety, sleep andseizure disorders, and overdoses of benzodiazepine-type drugs, andenhancing alertness.

2. Description of the Related Art

γ-Aminobutyric acid (GABA) is regarded as one of the major inhibitoryamino acid transmitters in the mammalian brain. Over 40 years haveelapsed since its presence in the brain was demonstrated (Roberts &Frankel, J. Biol. Chem 187: 55-63, 1950; Udenfriend, J. Biol. Chem. 187:65-69, 1950). Since that time, an enormous amount of effort has beendevoted to implicating GABA in the etiology of seizure disorders, sleep,anxiety and cognition (Tallman and Gallager, Ann. Rev. Neuroscience 8:21-44, 1985). Widely, although unequally, distributed through themammalian brain, GABA is said to be a transmitter at approximately 30%of the synapses in the brain. GABA mediates many of its actions througha complex of proteins localized both on cell bodies and nerve endings;these are called GABAa receptors. Postsynaptic responses to GABA aremediated through alterations in chloride conductance that generally,although not invariably, lead to hyperpolarization of the cell. Recentinvestigations have indicated that the complex of proteins associatedwith postsynaptic GABA responses is a major site of action for a numberof structurally unrelated compounds capable of modifying postsynapticresponses to GABA. Drugs that interact at the GABAa receptor can possessa spectrum of pharmacological activities depending on their abilities tomodify the actions of GABA.

1,4-Benzodiazepines, such as diazepam, flurazepam, and triazolamcontinue to be among the most widely used as anxiolytics,sedative-hypnotics, muscle relaxants, and anticonvulsants. A number ofthese compounds are extremely potent drugs; such potency indicates asite of action with a high affinity and specificity for individualreceptors. Early electrophysiological studies indicated that a majoraction of benzodiazepines was enhancement of GABAergic inhibition.Presently, those compounds possessing activity which enhance the effectof GABA are called agonists, those compounds which decrease the effectof GABA are called inverse agonists, and those compounds which block theeffect of GABA are called antagonists.

The GABAa receptor subunits have been cloned from bovine and human cDNAlibraries (Schoenfield et al., 1988; Duman et al., 1989). A number ofdistinct cDNAs were identified as subunits of the GABAa receptor complexby cloning and expression. These are categorized into α, β, γ, δ, ε, andprovide a molecular basis for the GABAa receptor heterogeneity anddistinctive regional pharmacology (Shivvers et al., 1980; Levitan etal., 1989). The γ subunit appears to enable drugs like benzodiazepinesto modify the GABA responses (Pritchett et al., 1989). The presence oflow Hill coefficients in the binding of ligands to the GABAa receptorindicates unique profiles of subtype specific pharmacological action.

With the discovery of the “receptor” for the benzodiazepines and thesubsequent definition of the nature of the interaction between GABA andthe benzodiazepines, it appears that the behaviorally importantinteractions of the benzodiazepines with different neurotransmittersystems are due in a large part to the enhanced ability of GABA itselfto modify these systems. Each modified system, in turn, may beassociated with the expression of a behavior. Depending on the mode ofinteraction, these compounds are capable of producing a spectrum ofactivities (either sedative, anxiolytic, and anticonvulsant, orwakefulness, seizures, and anxiety).

SUMMARY OF THE INVENTION

This invention provides novel compounds of Formula I which interact witha GABAa binding site, the benzodiazepine receptor.

The invention provides pharmaceutical compositions comprising compoundsof Formula I. The invention also provides compounds useful in thediagnosis and treatment of anxiety, sleep, and seizure disorders,overdose with benzodiazepine drugs and for enhancement of memory.Accordingly, a broad embodiment of the invention is directed tocompounds of Formula I:

wherein:

the C ring represents a carbocyclic group having from 5-7 members, whereany member of the carbocyclic group is optionally mono-, di-, ortrisubstituted with lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di (C₁-C₆)alkylamino, or trifluoromethyl;

X is hydrogen, hydroxy, or lower alkyl; and

W is lower alkyl optionally substituted with halogen, hydroxy, loweralkoxy, amino, or mono- or dialkyl amino where each alkyl portion islower alkyl; or

W is aryl, arylalkyl, or heteroaryl, where each aryl is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono-or dialkylamino where each alkyl portion is lower alkyl, mono- ordialkylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or C₀₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl, or NR₁R₂ form a 5, 6, or 7-memberedring having one ring member optionally replaced with oxygen or nitrogen.

These compounds are highly selective agonists, antagonists or inverseagonists for GABAa brain receptors or prodrugs of agonists, antagonistsor inverse agonists for GABAa brain receptors. These compounds areuseful in the diagnosis and treatment of anxiety, sleep and seizuredisorders, overdose with benzodiazepine drugs and for enhancement ofmemory.

DETAILED DESCRIPTION OF THE INVENTION

The novel compounds encompassed by the instant invention can bedescribed by general Formula I set forth above or the pharmaceuticallyacceptable non-toxic salts thereof.

In addition, the present invention also encompasses compounds of FormulaII:

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆, alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R_(b) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

n is an integer from 1-3; and

X is hydrogen or C₁-C₆ alkyl;

W is lower alkyl optionally substituted with halogen, hydroxy, loweralkoxy, amino, or mono- or dialkyl amino where each alkyl portion islower alkyl; or

W is aryl, arylalkyl, or heteroaryl, where each aryl is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,alkylaminoalkyl, preferably methylaminoalkyl, where each alkyl portionis lower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ arethe same or different and represent hydrogen or lower alkyl.

Preferred compounds of Formula II are where W is an optionallysubstituted aryl, arylalkyl, or heteroaryl. Other preferred compounds ofII are those where only one of R_(a) and R_(b) may be non-hydrogensubstituents; preferably the R_(a) and R_(b) groups are independentlyC₁-C₂ alkyl, or more preferably, hydrogen. Still other preferredcompounds of Formula II are those where X is C₁-C₆ alkyl or hydrogen,preferably hydrogen.

More preferred compounds of Formula II are where W is phenyl, benzyl,thienyl, thiazolyl, or pyridyl each of which is optionally substitutedwith one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl.

Even more preferred compounds of Formula II are W is phenyl, benzyl,thienyl, thiazolyl, or pyridinyl each of which is optionally substitutedwith one or two groups independently selected from halogen, hydroxy,lower alkyl, or lower alkoxy.

Other more preferred compounds of Formula II are those where the W groupis mono- or disubstituted with a halogen selected from chloro, bromo, orfluoro, amino, mono-or di(C₁-C₂)alkylamino (C₁-C₂)alkyl, C₁-C₃ alkoxy,C₁-C₃ alkyl, or hydroxy.

In addition, the present invention encompasses compounds of the FormulaIII:

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

W is lower alkyl optionally substituted with halogen, hydroxy, loweralkoxy, amino, or mono- or dialkyl amino where each alkyl portion islower alkyl; or

W is aryl, arylalkyl, or heteroaryl, where each aryl is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl.

Preferred compounds of Formula III are where W is an optionallysubstituted aryl, arylalkyl, or heteroaryl.

More preferred compounds of Formula III are where W is phenyl, benzyl,thiophene, thiazolyl, pyridinyl, or piperonyl each of which isoptionally substituted with one or two groups independently selectedfrom halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, loweralkoxy, amino, mono- or dialkylamino where each alkyl portion is loweralkyl, methylaminoalkyl where each alkyl portion is lower alkyl, orNR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same ordifferent and represent hydrogen or lower alkyl.

Even more preferred compounds of Formula III are where W is phenyl,benzyl, thiophene, thiazolyl, or pyridinyl each of which is optionallysubstituted with one or two groups independently selected from C₁-C₃alkyl, more preferably methyl, fluorine, or methoxy.

In addition, the present invention encompasses compounds of the FormulaIV.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

W is lower alkyl optionally substituted with halogen, hydroxy, loweralkoxy, amino, or mono- or dialkyl amino where each alkyl portion islower alkyl; or

W is aryl, arylalkyl, or heteroaryl, where each aryl is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl.

Preferred compounds of Formula IV are where W is an optionallysubstituted aryl, arylalkyl, or heteroaryl.

More preferred compounds of Formula IV are where W is phenyl, benzyl,thiophene, thiazolyl, pyridinyl, or piperonyl each of which isoptionally substituted with one or two groups independently selectedfrom halogen, trifluoromethyl, cyano, hydroxy, lower alkyl, loweralkoxy, amino, mono- or dialkylamino where each alkyl portion is loweralkyl, methyl or ethyl aminoalkyl where each alkyl portion is loweralkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the sameor different and represent hydrogen or lower alkyl.

Even more preferred compounds of Formula IV are where W is phenyl,benzyl, thiophene, thiazolyl, or pyridinyl each of which is optionallysubstituted with one or two groups independently selected from methyl,fluorine, hydroxy, or methoxy or C₁-C₃ alkyl, preferably methyl.

In addition, the present invention encompasses compounds of the FormulaV.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R_(b) is lower alkyl, C_(l)-C₆ alkoxy, hydroxy, halogen, amino, mono- ordi(C₁-C₆)alkylamino, or trifluoromethyl;

W is lower alkyl optionally substituted with halogen, hydroxy, loweralkoxy, amino, or mono- or dialkyl amino where each alkyl portion islower alkyl; or

W is aryl, arylalkyl, or heteroaryl, where each aryl is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl.

Preferred compounds of Formula V are where W is an optionallysubstituted aryl, arylalkyl, or heteroaryl.

More preferred compounds of Formula V are where W is phenyl, benzyl,thiazolyl, pyridinyl, or piperonyl each of which is optionallysubstituted with one or two groups independently selected from halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono-or dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, or NR₁COR₂,COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are the same or different andrepresent hydrogen or lower alkyl.

Even more preferred compounds of Formula IV are where W is phenyl,benzyl, or thiazolyl each of which is optionally substituted with one ortwo groups independently selected from chloro, fluoro, ethoxy ormethoxy.

Preferred compounds of the invention are encompassed by the followingformulae:

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R₃ and R₄ are the same or different and represent hydrogen, halogen,hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino whereeach alkyl portion is lower alkyl, methylaminoalkyl where each alkylportion is lower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ andR₂ are the same or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula VI are where R_(a) is hydrogen,methyl or ethyl, R₃ is hydrogen or halogen and R₄ is halogen, hydroxy,or lower alkoxy.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R₃ and R₄ are the same or different and represent hydrogen, halogen,hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino whereeach alkyl portion is lower alkyl, or methylaminoalkyl where each alkylportion is lower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ andR₂ are the same or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula VII are where R₃ is hydrogen orhalogen, R_(a) is hydrogen, methyl or ethyl, and R₄ is halogen, hydroxy,or lower alkoxy.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R₅ and R₆ are the same or different and represent hydrogen, halogen,hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino whereeach alkyl portion is lower alkyl, methylaminoalkyl where each alkylportion is lower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ andR₂ are the same or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula VIII are where R₅ is hydrogen orhalogen and R₆ is halogen, hydroxy, or lower alkoxy.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

R₅ and R₆ are the same or different and represent hydrogen, halogen,hydroxy, lower alkyl, lower alkoxy, amino, mono- or dialkylamino whereeach alkyl portion is lower alkyl, methylaminoalkyl where each alkylportion is lower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ andR₂ are the same or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula IX are where R₅ is hydrogen orhalogen and R₆ is halogen, hydroxy, or lower alkoxy.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each ofwhich may be independently substituted with halogen, hydroxyl, loweralkyl, lower alkoxy, amino, methylaminoalkyl where each alkyl portion islower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are thesame or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula X are where W is 2-, 3-, or4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which may beindependently substituted with halogen, lower alkyl, or lower alkoxy.

wherein:

R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl;

W is 2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each ofwhich may be independently substituted with halogen, hydroxyl, loweralkyl, lower alkoxy, amino, methylaminoalkyl where each alkyl portion islower alkyl, or NR₁COR₂, COR₂, CONR₁R₂ or CO₂R₂ where R₁ and R₂ are thesame or different and represent hydrogen or lower alkyl.

More preferred compounds of Formula X are where W is 2-, 3-, or4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which may beindependently substituted with halogen, lower alkyl, or lower alkoxy.

By “alkyl” and “lower alkyl” in the present invention is meant straightor branched chain alkyl groups having 1-6 carbon atoms, such as, methyl,ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl,2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and3-methylpentyl.

By “alkoxy” and “lower alkoxy” in the present invention is meantstraight or branched chain alkoxy groups having 1-6 carbon atoms, suchas, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy,sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy,hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.

By the term “halogen” in the present invention is meant fluorine,bromine, chlorine, and iodine.

By heteroaryl is meant one or more aromatic ring systems of 5-, 6-, or7-membered rings containing at least one and up to four heteroatomsselected from nitrogen, oxygen, or sulfur. Such heteroaryl groupsinclude, for example, thienyl, furanyl, thiazolyl, imidazolyl,(is)oxazolyl, pyridyl, pyrimidinyl, (iso)quinolinyl, napthyridinyl,benzimidazolyl, benzoxazolyl. Preferred heteroaryl groups are optionallysubstituted pyridyl, pyrimidinyl, naphthyridinyl, benzimidazolyl, andimidazolyl groups.

By aryl is meant an aromatic carbocyclic group having a single ring(e.g., phenyl), multiple rings (e.g., biphenyl), or multiple condensedrings in which at least one is aromatic, (e.g.,1,2,3,4-tetrahydronaphthyl, naphthyl, anthryl, or phenanthryl), which isoptionally mono-, di-, or trisubstituted with, e.g., halogen, loweralkyl, lower alkoxy, lower alkylthio, trifluoromethyl, lower acyloxy,aryl, heteroaryl, and hydroxy. Preferred aryl groups are optionallysubstituted phenyl and naphthyl groups.

Representative compounds of the invention are shown below in Table 1.

TABLE 1

1

3

5

6

11

13

14

15

20

23

27

39

40

41

42

43

44

Representative compounds of the present invention, which are encompassedby Formula I, include, but are not limited to the compounds in Table 1and their pharmaceutically acceptable salts. In addition, if thecompound of the invention is obtained as an acid addition salt, the freebase can be obtained by basifying a solution of the acid salt.Conversely, if the product is a free base, an addition salt,particularly a pharmaceutically acceptable addition salt, may beproduced by dissolving the free base in a suitable organic solvent andtreating the solution with an acid, in accordance with conventionalprocedures for preparing acid addition salts from base compounds.

Non-toxic pharmaceutically acceptable salts include salts of acids suchas hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic,toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric,maleic, hydroiodic, alkanoic such as acetic, HOOC—(CH₂)_(n)—COOH where nis 0-4, and the like. Those skilled in the art will recognize a widevariety of non-toxic pharmaceutically acceptable addition salts.

The present invention also encompasses the acylated prodrugs of thecompounds of Formula I. Those skilled in the art will recognize varioussynthetic methodologies which may be employed to prepare non-toxicpharmaceutically acceptable addition salts and acylated prodrugs of thecompounds encompassed by Formula I.

The compounds of Formula I and their salts are suitable for thediagnosis and treatment of anxiety, Down Syndrome, sleep, cognitive andseizure disorders, and overdose with benzodiazepine drugs and forenhancement of alertness, both in human and non-human animals anddomestic pets, especially dogs and cats and farm animals such as sheep,swine and cattle.

The compounds of general Formula I may be administered orally,topically, parenterally, by inhalation or spray or rectally in dosageunit formulations containing conventional non-toxic pharmaceuticallyacceptable carriers, adjuvants and vehicles. The term parenteral as usedherein includes subcutaneous injections, intravenous, intramuscular,intrasternal injection or infusion techniques. In addition, there isprovided a pharmaceutical formulation comprising a compound of generalFormula I and a pharmaceutically acceptable carrier. One or morecompounds of general Formula I may be present in association with one ormore non-toxic pharmaceutically acceptable carriers and/or diluentsand/or adjuvants and if desired other active ingredients. Thepharmaceutical compositions containing compounds of general Formula Imay be in a form suitable for oral use, for example, as tablets,troches, lozenges, aqueous or oily suspensions, dispersible powders orgranules, emulsion, hard or soft capsules, or syrups or elixirs.

Compositions intended for oral use may be prepared according to anymethod known to the art for the manufacture of pharmaceuticalcompositions and such compositions may contain one or more agentsselected from the group consisting of sweetening agents, flavoringagents, coloring agents and preserving agents in order to providepharmaceutically elegant and palatable preparations. Tablets contain theactive ingredient in admixture with non-toxic pharmaceuticallyacceptable excipients which are suitable for the manufacture of tablets.These excipients may be for example, inert diluents, such as calciumcarbonate, sodium carbonate, lactose, calcium phosphate or sodiumphosphate; granulating and disintegrating agents, for example, cornstarch, or alginic acid; binding agents, for example starch, gelatin oracacia, and lubricating agents, for example magnesium stearate, stearicacid or talc. The tablets may be uncoated or they may be coated by knowntechniques to delay disintegration and absorption in thegastrointestinal tract and thereby provide a sustained action over alonger period. For example, a time delay material such as glycerylmonosterate or glyceryl distearate may be employed.

Formulations for oral use may also be presented as hard gelatin capsuleswherein the active ingredient is mixed with an inert solid diluent, forexample, calcium carbonate, calcium phosphate or kaolin, or as softgelatin capsules wherein the active ingredient is mixed with water or anoil medium, for example peanut oil, liquid paraffin or olive oil.

Aqueous suspensions contain the active materials in admixture withexcipients suitable for the manufacture of aqueous suspensions. Suchexcipients are suspending agents, for example sodiumcarboxymethylcellulose, methylcellulose, hydropropylmethylcellulose,sodium alginate, polyvinylpyrrolidone, gum tragacanth and gum acacia;dispersing or wetting agents may be a naturally-occurring phosphatide,for example, lecithin, or condensation products of an alkylene oxidewith fatty acids, for example polyoxyethylene stearate, or condensationproducts of ethylene oxide with long chain aliphatic alcohols, forexample heptadecaethyleneoxycetanol, or condensation products ofethylene oxide with partial esters derived from fatty acids and ahexitol such as polyoxyethylene sorbitol monooleate, or condensationproducts of ethylene oxide with partial esters derived from fatty acidsand hexitol anhydrides, for example polyethylene sorbitan monooleate.The aqueous suspensions may also contain one or more preservatives, forexample ethyl, or n-propyl p-hydroxybenzoate, one or more coloringagents, one or more flavoring agents, and one or more sweetening agents,such as sucrose or saccharin.

Oily suspensions may be formulated by suspending the active ingredientsin a vegetable oil, for example arachis oil, olive oil, sesame oil orcoconut oil, or in a mineral oil such as liquid paraffin. The oilysuspensions may contain a thickening agent, for example beeswax, hardparaffin or cetyl alcohol. Sweetening agents such as those set forthabove, and flavoring agents may be added to provide palatable oralpreparations. These compositions may be preserved by the addition of ananti-oxidant such as ascorbic acid.

Dispersible powders and granules suitable for preparation of an aqueoussuspension by the addition of water provide the active ingredient inadmixture with a dispersing or wetting agent, suspending agent and oneor more preservatives. Suitable dispersing or wetting agents andsuspending agents are exemplified by those already mentioned above.Additional excipients, for example sweetening, flavoring and coloringagents, may also be present.

Pharmaceutical compositions of the invention may also be in the form ofoil-in-water emulsions. The oily phase may be a vegetable oil, forexample olive oil or arachis oil, or a mineral oil, for example liquidparaffin or mixtures of these. Suitable emulsifying agents may benaturally-occurring gums, for example gum acacia or gum tragacanth,naturally-occurring phosphatides, for example soy bean, lecithin, andesters or partial esters derived from fatty acids and hexitol,anhydrides, for example sorbitan monoleate, and condensation products ofthe said partial esters with ethylene oxide, for example polyoxyethylenesorbitan monoleate. The emulsions may also contain sweetening andflavoring agents.

Syrups and elixirs may be formulated with sweetening agents, for exampleglycerol, propylene glycol, sorbitor or sucrose. Such formulations mayalso contain a demulcent, a preservative and flavoring and coloringagents. The pharmaceutical compositions may be in the form of a sterileinjectable aqueous or oleaginous suspension. This suspension may beformulated according to the known art using those suitable dispersing orwetting agents and suspending agents which have been mentioned above.The sterile injectable preparation may also be sterile injectablesolution or suspension in a non-toxic parentally acceptable diluent orsolvent, for example as a solution in 1,3-butanediol. Among theacceptable vehicles and solvents that may be employed are water,Ringer's solution and isotonic sodium chloride solution. In addition,sterile, fixed oils are conventionally employed as a solvent orsuspending medium. For this purpose any bland fixed oil may be employedincluding synthetic mono- or diglycerides. In addition, fatty acids suchas oleic acid find use in the preparation of injectables.

The compounds of general Formula I may also be administered in the formof suppositories for rectal administration of the drug. Thesecompositions can be prepared by mixing the drug with a suitablenon-irritating excipient which is solid at ordinary temperatures butliquid at the rectal temperature and will therefore melt in the rectumto release the drug. Such materials are cocoa butter and polyethyleneglycols.

Compounds of general Formula I may be administered parenterally in asterile medium. The drug, depending on the vehicle and concentrationused, can either be suspended or dissolved in the vehicle.Advantageously, adjuvants such as local anaesthetics, preservatives andbuffering agents can be dissolved in the vehicle.

Dosage levels of the order of from about 0.1 mg to about 140 mg perkilogram of body weight per day are useful in the treatment of theabove-indicated conditions (about 0.5 mg to about 7 g per patient perday). The amount of active ingredient that may be combined with thecarrier materials to produce a single dosage form will vary dependingupon the host treated and the particular mode of administration. Dosageunit forms will generally contain between from about 1 mg to about 500mg of an active ingredient.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, and rate of excretion, drug combination and the severityof the particular disease undergoing therapy.

For administration to non-human animals, the composition may also beadded to the animal feed or drinking water. It will be convenient toformulate these animal feed and drinking water compositions with amullet-dose of the drug so that the animal takes in an appropriatequantity of the composition along with its diet. It will also beconvenient to present the composition as a premix for addition to thefeed or drinking water.

An illustration of the preparation of compounds of the present inventionis given in Scheme I. The appropriate pyridin-4-one-3-carboxylic acid isprepared essentially according to the procedures described in J. Het.Chem. 1975, 1245.

where the c-ring, X, and W carry the definitions given above for FormulaI.

Those having skill in the art will recognize that the starting materialsmay be varied and additional steps employed to produce compoundsencompassed by the present invention, as demonstrated by the followingexamples.

As shown in Scheme I, the appropriate pyridin-4-one-3-carboxylic acid istreated with an acid chloride, such as, for example, ethylchloroformate, in the presence of a base like triethylamine. Theresulting mixed anhydride is subsequently treated with an amine toafford the desired amide.

The disclosures in this application of all articles and references,including patents, are incorporated herein by reference.

The invention is illustrated further by the following examples which arenot to be construed as limiting the invention in scope or spirit to thespecific procedures described in them.

The starting materials and various intermediates may be obtained fromcommercial sources, prepared from commercially available organiccompounds, or prepared using well known synthetic methods.

Representative examples of methods for preparing intermediates of theinvention are set forth below.

EXAMPLE 1N-(4-Methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide

A quantity of 100 mg (0.61 mmole, 1.0 eq) of4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxylic acid isdissolved in 5 mL THF and 1 mL DMF and treated at 0° C. with 0.18 mL(1.2 mmole, 2.2 eq) TEA followed by 0.12 mL (1.2 mmole, 2.2 eq) of ethylchloroformate. The resulting solution is stirred for 30 min. at whichtime 0.17 mL (1.2 mmole, 2.2 eq) of 4-methoxybenzylamine is added. Thesolution is allowed to warm to room temperature for 1 hr before theaddition of 20 mL of H₂O, the THF is removed under reduced pressure, andthe resulting solid is filtered and washed with H₂O and then Et₂O. Theresulting solid is slurried in 1 mL EtOH and 5 mL 10% NaOH, warmed to90° C. for 10 min., cooled to 0° C., and pH adjusted to 9.0 with 3N HCl.The resulting solid is filtered, washed with H₂O, Et₂O, and purified bychromatography (silica gel, 10% CH₃OH/CH₂Cl₂), to yield 89 mg ofN-(4-Methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide(compound 1), mp 240-241° C.

EXAMPLE 2N-(2-Fluorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide

A quantity of 100 mg (0.52 mmole, 1.0 eq) of1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxylic acid is dissolved in 5mL THF and 1 mL DMF and treated at 0° C. with 0.16 mL (1.14 mmole, 2.2eq) TEA followed by 0.11 ml (1.14 mmole, 2.2 eq) of ethyl chloroformate.The resulting solution is stirred for 30 min at which time, 0.15 mL(1.14 mmole, 2.2 eq) of 4-methoxybenzyl amine is added. The solution isallowed to warm to room temperature for 1 hr before the addition 20 mLH₂O, the THF is removed under reduced pressure, and the resulting solidis filtered and washed with H₂O, then Et₂O, and purified bychromatography (silica gel, 10% CH₃OH/CH₂Cl₂), to yield 102 mg ofN-(2-Fluorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide(compound 5), mp 241-244° C.

EXAMPLE 3

The following compounds are prepared essentially according to theprocedures set forth in Examples 1 and 2.

(a)N-(4-methoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=241-244° C. (Compound 2).

(b)N-(2-thiazolyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=305° (dec.) (Compound 3).

(c)N-(phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=295-296° C. (Compound 4).

(d) N-(piperonyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=263-265° C. (Compound 6).

(e)N-(3-fluorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=319-320° C. (Compound 7).

(f) N-(phenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=299-300° C. (Compound 8).

(g) N-(2-thiazolyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=260° (dec.) (Compound 9).

(h)N-(4-methoxyphenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=287-290° C. (Compound 10).

(i)N-(4-methyl-2-thiazolyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=350-352° C. (Compound 11).

(j)N-(4-fluorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=324-326° C. (Compound 12).

(k) N-(3-pyridyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=308° (dec.) (Compound 13).

(l)N-(2-hydroxyphenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=295° (dec.) (Compound 14).

(m)N-(4-methoxypyrid-3-yl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=292° (dec.) (Compound 15).

(n)N-(3-methoxyphenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=275-280° C. (Compound 16).

(o)N-(4-methoxypyrid-2-yl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=312° (dec.) (Compound 17).

(p)N-(3-hydroxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=133-136° C. (Compound 18).

(q) N-(benzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=257-259° C. (Compound 19).

(r) N-(2-thienyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=306° (dec.) (Compound 20).

(s)N-(2-chlorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=339-341° C. (Compound 21).

(t) N-(3-thienyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=321-324° C. (Compound 22).

(u)N-(2,6-difluorophenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=278-280° C. (Compound 23).

(v)N-(2-methoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=217-219° C. (Compound 24).

(w)N-(3-methoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=210-212° C. (Compound 25).

(x)N-(2-fluorobenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=206-208° C. (Compound 26).

(y)N-(2-fluoro-4-methoxyphenyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=257-259° C. (Compound 27).

(z)N-(2-pyridyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=294-295° C. (Compound 28).

(aa)N-(4-methyl-2-thiazolyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=304-305° C. (Compound 29).

(bb)N-(3-fluorophenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=340° (dec.) (Compound 30).

(cc)N-(2-fluorophenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=330° (dec.) (Compound 31).

(dd)N-(2,4-difluorophenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=328° (dec.) (Compound 32).

(ee)N-(2,6-difluorophenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=297° (dec.) (Compound 33).

(ff)N-(benzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=149-150° C. (Compound 34).

(gg)N-(3-methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=204-205° C. (Compound 35).

(hh)N-(2-methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=243-244° C. (Compound 36).

(ii)N-(2,6-difluorobenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=294-295° C. (Compound 37).

(jj)N-(2-thienyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=210° (dec.) (Compound 38).

(kk)N-butyl-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=138-143° C. (Compound 39).

(ll)N-(2-thiazolyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=301° C. (dec.) (Compound 40).

(mm)N-(4-methoxyphenyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=240-242° C. (Compound 41).

(nn)N-(benzyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=224-226° C. (Compound 42).

(oo)N-(4-methoxybenzyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=203-205° C. (Compound 43).

(pp)N-(4-fluorobenzyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide;mp=219-222° C. (Compound 44).

(qq)N-(3-fluorobenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=267-270° C. (Compound 45).

(rr)N-(4-fluorobenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=278-280° C. (Compound 46).

(ss)N-(3-chlorobenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=247-249° C. (Compound 47).

(tt)N-(4-chlorobenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=283-285° C. (Compound 48).

(uu)N-(2-fluoro-4-methoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=257-259° C. (Compound 49).

(vv)N-(4-ethoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=241-243° C. (Compound 50).

(ww)N-(4-methylbenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=270-273° C. (Compound 51).

(xx)N-(3-methylbenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=242-245° C. (Compound 52).

(yy)N-(2-fluoro-4-ethoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=178-181° C. (Compound 53).

(zz)N-(2-fluoro-4-isopropoxybenzyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=197—200° C. (Compound 54).

(aaa)N-(2-fluoro-4-propyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=189-191° C. (Compound 55).

(bbb)N-(2-thienylmethyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide;mp=245-248° C. (Compound 56).

(ccc)N-(4-methoxyphenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=330-332° C. (Compound 57).

(ddd)N-(3-methoxyphenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=320° C. (dec.) (Compound 58).

(eee)N-(4-(2-hydroxyethoxy)phenyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=220-222° C. (Compound 59).

(fff)N-((4-(dimethylamino)phenyl)methyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-4-3-carboxamide;mp=269-270° C. (Compound 60).

(ggg)N-(2-fluoro-4-methoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-4-3-carboxamide;mp=238-240° C. (Compound 61).

(hhh)N-(4-ethoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-4-3-carboxamide;mp=243-245° C. (Compound 62).

(iii)N-(2-fluoro-4-ethoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=217-219° C. (Compound 63).

(jjj)N-(2-fluoro-4-isopropoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=214° C. (dec.) (Compound 64).

(kkk)N-(2-fluoro-4-propoxybenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=209-211° C. (Compound 65).

(lll)N-(2-fluorobenzyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide;mp=259-261° C. (Compound 66).

EXAMPLE 4

The pharmaceutical utility of compounds of this invention are indicatedby the following assay for GABAa receptor activity.

Assays are carried out as described in Thomas and Tallman (J. Bio. Chem.156: 9838-9842 , J. Neurosci. 3: 433-440, 1983). Rat cortical tissue isdissected and homogenized in 25 volumes (w/v) of 0.05 M Tris HCl buffer(pH 7.4 at 4° C.). The tissue homogenate is centrifuged in the cold (4°)at 20,000×g for 20′. The supernatant is decanted and the pellet isrehomogenized in the same volume of buffer and again centrifuged at20,000×g. The supernatant is decanted and the pellet is frozen at −20°C. overnight. The pellet is then thawed and rehomogenized in 25 volume(original wt/vol) of buffer and the procedure is carried out twice. Thepellet is finally resuspended in 50 volumes (w/vol of 0.05 M Tris HClbuffer (pH 7.4 at 40° C.).

Incubations contain 100 ml of tissue homogenate, 100 ml of radioligand0.5 nM (³H-RO15-1788 [³H-Flumazenil] specific activity 80 Ci/mmol), drugor blocker and buffer to a total volume of 500 ml. Incubations arecarried for 30 min at 4° C. then are rapidly filtered through GFBfilters to separate free and bound ligand. Filters are washed twice withfresh 0.05 M Tris HCl buffer (pH 7.4 at 4° C.) and counted in a liquidscintillation counter. 1.0 mM diazepam is added to some tubes todetermine nonspecific binding. Data are collected in triplicatedeterminations, averaged and % inhibition of total specific binding iscalculated. Total Specific Binding=Total−Nonspecific. In some cases, theamounts of unlabeled drugs is varied and total displacement curves ofbinding are carried out. Data are converted to a form for thecalculation of IC₅₀ and Hill Coefficient (nH). In the described assayscompounds have Ki's of less than 1 μM.

EXAMPLE 5

In addition, the following assay may be used to determine if thecompounds of the invention are agonists, antagonists, or inverseagonists, and, therefore, their specific pharmaceutical utility. Thefollowing assay can be employed to determine specific GABAa receptoractivity.

Assays are carried out as described in White and Gurley (NeuroReport 6:1313-1316, 1995) and White, Gurley, Hartnett, Stirling, and Gregory(Receptors and Channels 3: 1-5, 1995) with modifications. Xenopus Laevisoocytes are enzymatically isolated and injected with non-polyadenylatedcRNA mixed in a ratio of 4:1:4 for human derived α, β, and γ subunits,respectively. For each subunit combination, sufficient message isinjected to result in current amplitudes of >10 nA when 1 μM GABA isapplied.

Electrophysiological recordings are carried out using the two electrodevoltage-clamp technique at a membrane holding potential of −70 mV.

Compounds are evaluated against a GABA concentration that evokes <10% ofthe maximal evokable GABA current. Each oocyte is exposed to increasingconcentrations of compound in order to evaluate a concentration/effectrelationship. Compound efficacy is expressed as a percent-change incurrent amplitude: 100*((Ic/I)−1), where Ic is the GABA evoked currentamplitude observed in the presence of compound and I is the GABA evokedcurrent amplitude observed in the absence of compound.

Specificity of a compound for the Ro15-1788 site is determined followingcompletion of the concentration/effect curve. After washing the oocytesufficiently to remove previously applied compound, the oocyte isexposed to GABA+1 μM Ro15-1788, followed by exposure to GABA+1 μMRo15-1788+ compound. Percent change due to addition of compound iscalculated as described above. Any percent change observed in thepresence of Ro15-1788 is subtracted from the percent changes in currentamplitude observed in the absence of 1 μM Ro15-1788. These net valuesare used for the calculation of average efficacy and EC₅₀ values.

To evaluate average efficacy and EC₅₀ values, the concentration/effectdata are averaged across cells and fit to the logistic equation. Averagevalues are reported as mean ± standard error.

The invention and the manner and process of making and using it, are nowdescribed in such full, clear, concise and exact terms as to enable anyperson skilled in the art to which it pertains, to make and use thesame. It is to be understood that the foregoing describes preferredembodiments of the present invention and that modifications may be madetherein without departing from the spirit or scope of the presentinvention as set forth in the claims. To particularly point out anddistinctly claim the subject matter regarded as invention, the followingclaims conclude this specification.

What is claimed is:
 1. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: theC ring represents a carbocyclic group having from 5-7 members, where anymember of the carbocyclic group is optionally substituted with loweralkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino, mono- ordi(C₁-C₆)alkylamino, or trifluoromethyl; X is hydrogen, hydroxy, orlower alkyl,; and W is heteroaryl where each heteroaryl is optionallysubstituted with one or two groups independently selected from the groupconsisting of halogen, trifluoromethyl, cyano, hydroxy, lower alkyl,lower alkoxy, amino, mono- or dialkylamino where each alkyl portion islower alkyl, methylaminoalkyl where each alkyl portion is lower alkyl,and a carbonyl containing group selected from NR₁COR₂, COR₂, CONR₁R₂ andCO₂R₂ where R₁ and R₂ are the same or different and represent hydrogenor lower alkyl.
 2. A compound of the formula:

or a pharmaceutically acceptable salt thereof wherein: W is heteroaryl,where each heteroaryl is optionally substituted with one or two groupsindependently selected from a group consisting of halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono-or dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, and a carbonylcontaining group selected from NR₁COR₂, COR₂, CONR₁R₂ and CO₂R₂ where R₁and R₂ are the same or different and represent hydrogen or lower alkyl.3. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: W isheteroaryl, where each heteroaryl is optionally substituted with one ortwo groups independently selected from a group consisting of halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, mono-or dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, and a carbonylcontaining group selected from NR₁COR₂, COR₂, CONR₁R₂ and CO₂R₂ where R₁and R₂ are the same or different and represent hydrogen or lower alkyl.4. A compound according to claim 1 which is:

or the pharmaceutically acceptable non-toxic salts thereof wherein: W is2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which maybe independently substituted with halogen, hydroxyl, lower alkyl, loweralkoxy, amino, methylaminoalkyl where each alkyl portion is lower alkyl,or a carbonyl containing group selected from NR₁COR₂, COR₂, CONR₁R₂ andCO₂R₂ where R₁ and R₂ are the same or different and represent hydrogenor lower alkyl.
 5. A compound according to claim 1 which is:

or the pharmaceutically acceptable non-toxic salts thereof wherein: W is2-, 3-, or 4-pyridyl, 2- or 3-thienyl, or 2-thiazolyl, each of which maybe independently substituted with halogen, hydroxyl, lower alkyl, loweralkoxy, amino, methylaminoalkyl where each alkyl portion is lower alkyl,a carbonyl containing group selected from NR₁COR₂, COR₂, CONR₁R₂ andCO₂R₂ where R₁ and R₂ are the same or different and represent hydrogenor lower alkyl.
 6. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein:R_(a) is hydrogen, lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino,mono- or di(C₁-C₆)alkylamino, or trifluoromethyl; R_(b) is hydrogen,lower alkyl, C₁-C₆ alkoxy, hydroxy, halogen, amino, mono- ordi(C₁-C₆)alkylamino, or trifluoromethyl; n is an integer from 1-3; and Wis heteroaryl, where each heteroaryl is optionally substituted with oneor two groups independently selected from a group consisting of halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, and a carbonylcontaining group selected from NR₁COR₂, COR₂, CONR₁R₂ and CO₂R₂ where R₁and R₂ are the same or different and represent hydrogen or lower alkyl.7. A compound of the formula:

or the pharmaceutically acceptable non-toxic salts thereof wherein: W isheteroaryl, where each heteroaryl is optionally substituted with one ortwo groups independently selected from a group consisting of halogen,trifluoromethyl, cyano, hydroxy, lower alkyl, lower alkoxy, amino, monoor dialkylamino where each alkyl portion is lower alkyl,methylaminoalkyl where each alkyl portion is lower alkyl, and a carbonylcontaining group selected from NR₁COR₂, COR₂, CONR₁R₂ and CO₂R₂ where R₁and R₂ are the same or different and represent hydrogen or lower alkyl.8. A compound according to claim 1 which isN-(2-thiazolyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide.9. A compound according to claim 1 which isN-(2-thiazolyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.
 10. Acompound according to claim 1 which isN-(4-methyl-2-thiazolyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.11. A compound according to claim 1 which isN-(3-pyridyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.
 12. Acompound according to claim 1 which isN-(4-methoxypyrid-3-yl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.13. A compound according to claim 1 which isN-(4-methoxypyrid-2-yl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.14. A compound according to claim 1 which isN-(2-thienyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.
 15. Acompound according to claim 1 which isN-(3-thienyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.
 16. Acompound according to claim 1 which isN-(2-pyridyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide.17. A compound according to claim 1 which isN-(4-methyl-2-thiazolyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide.18. A compound according to claim 1 which isN-(2-thienyl)-4,5,6,7-tetrahydro-1H-cyclopenta[b]pyridin-4-one-3-carboxamide.19. A compound according to claim 1 which isN-(2-thiazolyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide.20. A compound according to claim 1 which isN-(2-thiazolyl)-4,5,6,7,8,9-hexahydro-1H-cyclohepta[b]pyridin-4-one-3-carboxamide.21. A compound according to claim 1 which isN-(2-thienylmethyl)-1,4,5,6,7,8-hexahydroquinolin-4-one-3-carboxamide.22. A compound according to claim 1, wherein the heteroaryl isthiazolyl, pyridyl, or thienyl.